tbuckley/cabot-search huggingface dataset:
P786: ANTI-PD-1 ANTIBODY (SINTILIMAB) PLUS DECITABINE AS FIRST LINE TREATMENT FOR PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME（MDS）: PRELIMINARY RESULTS FROM A SINGLE-ARM, OPEN-LABEL, PHASE II STUDY
Authors: J. wang, S. li, H. Jiang, Y. Chang, X. Zhao, J. Jia, X. Zhu, L. Gong, X. Liu, W. Yu, X. Huang
Journal: HemaSphere (2022)

Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients (pts) with higher-risk MDS, but the survival of pts after HMAs treatment is poor. It has been demonstrated that the PD-1/PD-L1 expression was upregulated by HMAs in MDS pts, providing a strong rationale for combining HMAs with PD-1 antibody for MDS treatment. Aims: To evaluate safety and efficacy of Sintilimab plus decitabine for pts with higher-risk MDS in a single-arm, open-label,phase 2 study(ChiCTR2100044393). Methods: Adult pts with higher-risk MDS by the IPSS-R were enrolled. Patients received decitabine 20mg/m2 intravenously daily for 5 days and sintilimab 200mg IV starting on the first and 22nd day of a cycle every 42 days until unacceptable toxicity, relapse, or progression, for a maximum of 8 cycles. The primary endpoint was overall response rate (CR+PR+mCR). Simon’s optimal two-stage design was employed.If five or more pts in stage I (13 pts) achieved ORR, the study would enroll 34 additional pts in stage II (47 pts).Secondary endpoints included safety, and survival outcomes. The relationship between expression levels of immune-checkpoint and efficacy of the combination therapy, as well as other potential biomarkers were also explored via genomic profiling. Results: At data cut-off (February 22, 2022), 21 pts were enrolled with a median follow-up time of 6.5 months. The median age of pts was 64 years (range 30-83), and the other characteristics are summarised in Table 1.The ORR was 62%, with six pts reaching complete response (CR),four pts reaching marrow CR and three pts achieved marrow CR+ hematologic improvement (HI). In addition,four pts reaching HI,so the overall improvement rate was 81%. The most common grade 3 treatment-emergent adverse events(TEAEs)(>10%) were febrile neutropenia (76.2%) and pulmonary infection (38.1%). No grade 4 TEAEs and treatment-related deaths occurred. A total of 12 pts （57.1%）experienced immune-related adverse event, including rash (28.6%), pneumonia (9.5%), hypothyroidism (9.5%), elevated serum bilirubin (4.8%) and transpeptidase (4.8%), which were all resolved by glucocorticoid. In these 21 pts, the most frequently mutated genes are ASXL1（28.6%）， RUNX1 (14.3%) and TET2(14.3%). Updated biomarker data will be presented during the EHA meeting. Image:Summary/Conclusion: To the best of our knowledge, this is the first study to evaluate the efficacy and safety of sintilimab plus decitabine in pts with untreated higher-risk MDS. The preliminary results demonstrate that the combination therapy is relatively safe with anti-tumor activity.
GREPore-Seq: A Robust Workflow to Detect Changes After Gene Editing Through Long-Range PCR and Nanopore Sequencing
Authors: Zi-Jun Quan, Si-Ang Li, Zhi-Xue Yang, Juan-Juan Zhao, Guo-Hua Li, Feng Zhang, Wei Wen, Tao Cheng, Xiao-Bing Zhang
Journal: Genomics Proteomics & Bioinformatics (2022)

To achieve the enormous potential of gene-editing technology in clinical therapies, one needs to evaluate both the on-target efficiency and unintended editing consequences comprehensively. However, there is a lack of a pipelined, large-scale, and economical workflow for detecting genome editing outcomes, in particular insertion or deletion of a large fragment. Here, we describe an approach for efficient and accurate detection of multiple genetic changes after CRISPR/Cas9 editing by pooled nanopore sequencing of barcoded long-range PCR products. Recognizing the high error rates of Oxford nanopore sequencing, we developed a novel pipeline to capture the barcoded sequences by grepping reads of nanopore amplicon sequencing (GREPore-seq). GREPore-seq can assess nonhomologous end-joining (NHEJ)-mediated double-stranded oligodeoxynucleotide (dsODN) insertions with comparable accuracy to Illumina next-generation sequencing (NGS). GREPore-seq also reveals a full spectrum of homology-directed repair (HDR)-mediated large gene knock-in, correlating well with the fluorescence-activated cell sorting (FACS) analysis results. Of note, we discovered low-level fragmented and full-length plasmid backbone insertion at the CRISPR cutting site. Therefore, we have established a practical workflow to evaluate various genetic changes, including quantifying insertions of short dsODNs, knock-ins of long pieces, plasmid insertions, and large fragment deletions after CRISPR/Cas9-mediated editing. GREPore-seq is freely available at GitHub (https://github.com/lisiang/GREPore-seq) and the National Genomics Data Center (NGDC) BioCode (https://ngdc.cncb.ac.cn/biocode/tools/BT007293).
Biased Study Design and Statistical Analysis in a Need for Intensive Care Unit Admission Surgical Prediction Model—Reply
Authors: William G. Henderson, Paul D. Rozeboom, Robert A. Meguid
Journal: JAMA Surgery (2022)

In Reply We wish to thank Roepke and Besen for their interest in our recent publication1 and reply to their comments. The purpose of our study was to determine if we could accurately predict need for postoperative intensive care unit (ICU) use at our institution.
P1223: PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A RETROSPECTIVE STUDY OF THE ZRMA REGIMEN（ZANUBRUTINIB, RITUXIMAB, METHOTREXATE AND CYTARABINE)
Authors: Y. Tang
Journal: HemaSphere (2022)

Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma that affects the brain, eyes, cerebrospinal fluid (CSF), or spinal cord without systemic involvement. Current treatments including surgery, chemotherapy and whole-brain radiotherapy often fail to achieve satisfactory effect, especially in elderly. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis including activation of the B-cell receptor pathway.Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib has been tested in clinical trials against R/R PCNSL and shows potential to be used in first-line treatment of PCNSL. Aims: To evaluate efficacy and safety of Zanubrutinib, rituximab, methotrexate and cytarabine(ZRMA regimen) in patients with primary CNS diffuse large b cell lymphoma. Methods: Retrospective study was done on patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease who received ZRMA regimen in our hospital.Patients received four courses of ZRMA regimen every 21 days a cycle: Zanubrutinib 80mg twice daily, rituximab 375 mg/m(2) on days 0,methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) once daily on days 2. Patients with responsive were then received whole-brain radiotherapy, autologous stem cell transplantation or lenalidomide maintenance. Results: Between Aug 18, 2020, and Feb 28, 2022, 15 enrolled patients were assessable. At median follow-up of 10 months（3-18）, patients had a complete remission rate of 93%(14/15). The median progression-free survival (PFS) and overall survival (OS) was not reached. The only two grade 3-4 adverse events were neutropenia(7%,1/15) and f infections(7%,1/15). The ZRMA regimen was well tolerated in these treatment-naïve PCNSL patients with an acceptable safety profile. Summary/Conclusion: This retrospective study provides an evidence supporting the use of ZRMA regimen for further research in patients aged up to 70 years with newly diagnosed primary CNS lymphoma.
Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence
Authors: Julia A. Belk, Winnie Yao, Nghi Ly, Katherine A. Freitas, Yan-Ting Chen, Quanming Shi, Alfredo M. Valencia, Eric Shifrut, Nupura Kale, Kathryn E. Yost, Connor V. Duffy, Bence Daniel, Madeline A. Hwee, Zhuang Miao, Alan Ashworth, Crystal L. Mackall, Alexander Marson, Julia Carnevale, Santosh A. Vardhana, Ansuman T. Satpathy
Journal: Cancer Cell (2022)
Industry sponsorship bias in cost effectiveness analysis: registry based analysis
Authors: Feng Xie, Ting Zhou
Journal: BMJ (2022)

To assess the association between industry sponsorship (drug, medical device, and biotechnology companies) and cost effectiveness results in cost effectiveness analysis (CEA).Registry based analysis DATA SOURCE: The Tufts Cost-Effectiveness Analysis Registry was used to identify all CEAs published in Medline between 1976 and 2021.CEAs that reported incremental cost effectiveness ratio (ICER) using quality adjusted life year and provided sufficient information about the magnitude or location of the ICER.Descriptive analyses were used to describe and compare the characteristics of CEAs with and without industry sponsorship. Logistic regression was used to identify the association between industry sponsorship and the cost effective conclusion using selected threshold values ($50 000 (£40 511; €47 405), $100 000, and $150 000). Robust linear regression was used to assess the association between industry sponsorship and the magnitude of ICER. All regression analyses were adjusted for disease and study design characteristics.8192 CEAs were eligible and included in the analysis, with 2437 (29.7%) sponsored by industry. Industry sponsored CEAs were more likely to publish ICERs below $50 000 (adjusted odds ratio 2.06, 95% confidence interval 1.82 to 2.33), $100 000 (2.95, 2.52 to 3.44), and $150 000 (3.34, 2.80 to 3.99) than non-industry sponsored studies. Among 5877 CEAs that reported positive incremental costs and quality adjusted life years, ICERs from industry sponsored studies were 33% lower (95% confidence interval -40 to -26) than those from non-industry sponsored studies.Sponsorship bias in CEAs is significant, systemic, and present across a range of diseases and study designs. Use of CEAs conducted by independent bodies could provide payers with more ability to negotiate lower prices. This impartiality is especially important for countries that rely on published CEAs to inform policy making for insurance coverage because of limited capacity for independent economic analysis.
P668: ACALABRUTINIB VS RITUXIMAB PLUS IDELALISIB OR BENDAMUSTINE IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA: ASCEND RESULTS AT ~4 YEARS OF FOLLOW-UP
Authors: P. Ghia, A. Pluta, M. Wach, D. Lysak, M. Simkovic, I. Kriachok, A. Illes, J. de la Serna, S. Dolan, P. Campbell, G. Musuraca, A. Jacob, E. Avery, J. H. Lee, G. Usenko, M. H. Wang, T. Yu, W. Jurczak
Journal: HemaSphere (2022)

Background: Acalabrutinib (acala) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for patients (pts) with chronic lymphocytic leukemia (CLL). In the primary analysis of ASCEND (median follow-up 16.1 mo), acala showed superior efficacy with an acceptable tolerability profile vs idelalisib (Id) plus rituximab (R) (IdR) or bendamustine (B) plus R (BR) in pts with relapsed/refractory (R/R) CLL (Ghia et al. J Clin Oncol. 2020;38:2849-2861). Aims: We report the results of the ASCEND study at ~4 years of follow-up. Methods: In this multicenter, randomized, open-label, phase 3 study (NCT02970318), pts with R/R CLL received oral (PO) acala 100 mg BID until progression or unacceptable toxicity or investigator’s (INV) choice of IdR (Id: 150 mg PO BID until progression or unacceptable toxicity; R: 375 mg/m2 x1 then 500 mg/m2 IV [8 total infusions]) or BR (B: 70 mg/m2 IV; R: 375 mg/m2 x1 then 500 mg/m2 IV [6 cycles]). Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed. Results: A total of 310 pts (acala, n=155; IdR, n=119; BR, n=36) were randomized (median age 67 y; del(17p) 15%, unmutated IGHV 74%, Rai stage 3/4 42%). At median follow-up of 46.5 mo (acala) and 45.3 mo (IdR/BR), acala significantly prolonged INV-assessed PFS vs IdR/BR (median not reached [NR] vs 16.8 mo; P<0.0001); 42-mo PFS rates were 62% for acala vs 19% for IdR/BR. In pts with del(17p), median PFS was NR (acala) vs 13.8 mo (IdR/BR; P<0.0001). In pts with unmutated IGHV, median PFS was NR (acala) vs 16.2 mo (IdR/BR; P<0.0001). Median OS was NR in both arms; 42-mo OS rates were 78% (acala) vs 65% (IdR/BR). ORR was 83% (acala) vs 84% (IdR/BR) (ORR + partial response with lymphocytosis: 92% [acala] vs 88% [IdR/BR]). AEs led to drug discontinuation in 23% of acala, 67% of IdR, and 17% of BR pts. Events of clinical interest (acala vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), and grade ≥3 infections (29% vs 29%). Image:Summary/Conclusion: At ~4 years of follow-up, acala maintained efficacy compared with standard-of-care regimens and a consistent tolerability profile in R/R CLL.
S242: EARLY INFUSION OF MSCS IN THE PROPHYLAXIS OF GVHD AFTER HAPLO-HEMATOPOIETIC STEM-CELL TRANSPLANTATION
Authors: R. Huang, T. Chen, S. Wang, J. Wang, Y. Su, J. Liu, Q. Wen, P. Kong, C. Zhang, L. Gao, L. Gao, X. Zhang
Journal: HemaSphere (2022)

Background: After the efficiency of repeated infusion umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in preventing chronic graft versus host disease (GVHD) from 100 days after haploidentical hematopoietic stem-cell transplantation (haplo-HSCT) was proved in the last trial, we design a sequel clinical trial to further explore the early repeated infusion of UC-MSCs in GVHD prophylaxis. Aims: To evaluate the efficacy of repeated infsion of MSCs in GVHD prophylaxis from D45 after haplo-HSCT. Methods: 128 qualified subjects aged between 18 and 60 with haplo-HSCT in five transplant centers in Mid-West of China were enrolled and randomly assigned equally into the MSCs group and the control group. Patients in the MSCs group received 4 rounds infusion of UC-MSCs (1×106 cells/kg per two weeks from 45 days after transplantation). We investigated the incidence of GVHD and relapse free survival (GRFS), the incidence and severity of aGVHD and cGVHD and the accumulative relapse rate. Results: The one-year GRFS in the MSCs group is 65.6% in the MSCs group, which is significantly higher than the control group (43.7%, P= 0.0129). The accumulative incidence of III-IV aGVHD and severe cGVHD of patients in the MSCs group significantly decreased, which is 3.1% and 6.3%, while the control group is 25.6% and 18.8% (P=0.0089 and P=0.0260). The MSCs infusion did not influence the accumulative relapse rate, which is 10.9% in both groups. Image:Summary/Conclusion: In this trial, we proved that early repeated infusion of UC-MSCs could effectively improve the GRFS rate for patients after haplo-HSCT by decreasing the incidence and severity of GVHD without increasing the incidences of relapse for these patients.
Exposure to Per- and Polyfluoroalkyl Substances and Mortality in U.S. Adults: A Population-Based Cohort Study
Authors: Xue Wen, Mei Wang, Xuewen Xu, Tao Li
Journal: Environmental Health Perspectives (2022)

Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants associated with diseases such as cancer and dyslipidemia. However, few studies have investigated the association between PFAS mixture exposure and mortality in general populations.This study aimed to explore the association between PFAS mixture, perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS) and mortality in U.S. adults by a nationally representative cohort.Adults ≥18 years of age who were enrolled in the National Health and Nutrition Examination Survey (NHANES) (1999-2014) were included in our study. Baseline serum concentrations of seven PFAS were measured and individuals were followed up to 31 December 2015. Hazard ratios (HRs) and confidence intervals (CIs) were estimated using Cox proportional hazards models. Association between PFAS mixture exposure and mortality was analyzed using the k-means method by clustering PFAS mixtures into subgroups. Association between PFOA/PFOS exposure and mortality was subsequently analyzed in both continuous and categorical models.During the follow-up period, 1,251 participants died. In the mixture analysis, the k-means algorithm clustered participants into low-, medium-, and high-exposure groups. Compared with the low-exposure group, participants in the high-exposure group showed significantly higher risks for all-cause mortality (HR=1.38; 95% CI: 1.07, 1.80), heart disease mortality (HR=1.58; 95% CI: 1.05, 2.51), and cancer mortality (HR=1.70; 95% CI: 1.08, 2.84). In single PFAS analysis, PFOS was found to be positively associated with all-cause mortality (third vs. first tertile HR=1.57; 95% CI: 1.22, 2.07), heart disease mortality (third vs. first tertile HR=1.65; 95% CI: 1.09, 2.57), and cancer mortality (third vs. first tertile HR=1.75; 95% CI: 1.10, 2.83), whereas PFOA exposure had no significant association with mortality. Assuming the observed association is causal, the number of deaths associated with PFOS exposure (≥17.1 vs. <7.9 ng/mL) was ∼382,000 (95% CI: 176,000, 588,000) annually between 1999 and 2015, and it decreased to 69,000 (95% CI: 28,000, 119,000) annually between 2015 and 2018. The association between PFOS and mortality was stronger among women and people without diabetes.We observed a positive association between PFAS mixture exposure and mortality among U.S. adults. Limitations of this study include the potential for unmeasured confounding, selection bias, a relatively small number of deaths, and only measuring PFAS at one point in time. Further studies with serial measures of PFAS concentrations and longer follow-ups are necessary to elucidate the association between PFAS and mortality from specific causes. https://doi.org/10.1289/EHP10393.
P1413: TRANSCRIPTION FACTOR-DRIVEN COORDINATION OF CELL CYCLE EXIT AND SPECIFICATION OF CELL IDENTITY IN VIVO DURING GRANULOCYTIC DIFFERENTIATION - IN MEMORIAM PROF. NIELS BORREGAARD
Authors: K. Theilgaard-Mönch, S. Pundhir, K. Kristian Reckzeh, J. Su, M. Tapia, B. Furtwängler, J. Jendholm, J. Schou Jakobsen
Journal: HemaSphere (2022)

Background: Differentiation of multi-potent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues and organs such as the hematopoietic system. This process requires temporal coupling of cell cycle exit and differentiation and is tightly coordinated by regulatory networks inhibiting cell cycle master regulators concomitant with activation of distinct transcriptional programs defining the identity of tissue-specific cell types. Aims: The current study investigated the regulatory mechanisms of how tissue-specific transcription factors (i.e. CEBPA and CEBPE) coordinate cell cycle exit, lineage-specification and terminal dofferentiation during in vivo hematopoietic development (i.e. granulocytic differentiation). Methods: For the current study we implemented a novel hierarchy of fifteen immunophenotypically defined differentiation stages, which refined the granulocytic and monocytic differentiation hierarchies at a hitherto unprecedented resolution. We purified these differentiations stages from CEBPA/CEBPE WT and KO mice and conducted global mRNA-seq and CEBPA/CEBPE ChIP-seq analyses, as well as complementary mechanistic validation experiments. Results: Our study demonstrates that CEBPA promotes lineage-specification by launching a full enhancer-primed differentiation program and by activation of CEBPE expression. Subsequently, CEBPE takes over and directs sequential promotor-driven cell cycle exit by (i) launching a MYC – MAD switch leading to inhibition of G1/S gene expression, (ii) repression of E2F-meditated G2/M gene expression, and (iii) up-regulation of Cdk1/2/4inhibitors. After cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program at the enhancer level to generate fully mature granulocytes. Summary/Conclusion: Our study highlights that tissue-specific transcription factors regulate cell cycle exit at the promotor level and lineage-specification and terminal differentiation at the enhancer level during hematopoietic development. In a broader perspective, our study contributes to the understanding of the temporal regulatory mechanisms of normal tissue development and homeostasis, which might have impact on the development of novel differentiation therapies for patients suffering from malignant and non-malignant diseases with impaired transcriptional differentiation programs.
Hepatic encephalopathy
Authors: Dieter Häussinger, Radha K. Dhiman, Vicente Felipo, Boris Görg, Rajiv Jalan, Gerald Kircheis, Manuela Merli, Sara Montagnese, Manuel Romero-Gomez, Alfons Schnitzler, Simon D. Taylor-Robinson, Hendrik Vilstrup
Journal: Nature Reviews Disease Primers (2022)
Environmental Outcomes Associated With Transition From In-Person to a Virtual Oncology Conference During the COVID-19 Pandemic
Authors: Katie E. Lichter, Taylor Drew, Sasha Demeulenaere, Emily Wong, Osama Mohamad, Sue S. Yom, Hilary P. Bagshaw
Journal: JAMA Oncology (2022)

This cohort study characterizes the potential environmental benefit associated with the transition from in-person professional conference attendance to virtual conference attendance before and during the COVID-19 pandemic.
Real-time, in vivo skin cancer triage by laser-induced plasma spectroscopy combined with a deep learning–based diagnostic algorithm
Authors: Sung Hyun Pyun, Wanki Min, Boncheol Goo, Samuel Seit, Anthony Azzi, David Yu-Shun Wong, Girish S. Munavalli, Chang-Hun Huh, Chong-Hyun Won, Minsam Ko
Journal: Journal of the American Academy of Dermatology (2022)